There are data documenting that pretreatment with lithium (Li) maximizes the uptake and residence time of radioactive iodine (RAI) in the metastatic differentiated thyroid cancer (DTC) lesions, without the established effect on the outcome. The goal of our study was to compare the efficacy of the three methods of preparation for dosimetry-based RAI therapy of metastatic DTC: recombinant human TSH (rhTSH), thyroid hormone withdrawal (THW), THW with pre-treatment with Lithium for 7 days (THW+Li). We performed a retrospective analysis of metastatic DTC patients treated with dosimetry-based RAI, divided into 3 groups: rhTSH, THW and THW+Li. The primary outcome was overall survival (OS) and progression free survival (PFS). Kaplan-Meier survival analyses were performed to compare time to progression and death between the groups. Cox proportional hazards regression model was performed to study the contribution of age, TNM status and location of distant metastases. The study cohort consisted of 135 patients (82 women, 53 men) treated with average cumulative RAI activity of 550+/-393 mCi and prepared for RAI with rhTSH (n=42), THW (n=52) and THW+Li (n=41). During the follow up of 7.1+/-7.6 years, 49.6% of patients (67/135) had disease progression and 11.8% of patients (n=16/135) died. We documented that pretreatment with Lithium was associated with improved OS in patients with metastatic DTC, but the contribution of age and presence of widespread disease with metastases to the brain and spine were more important factors associated with decreased OS and PFS. We also assess the role of the suppression of thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) with levothyroxine used in management of intermediate- and high-risk differentiated thyroid cancer (DTC) to reduce the likelihood of progression and deat. This cohort study used a multicenter database analysis including patients from tertiary referral centers and local clinics followed up for a mean (SD) of 7.2 (5.8) years. Patients with DTC treated uniformly with total thyroidectomy and radioactive iodine between January 1, 1979, and March 1, 2015, were included. Among the 1012 patients, 145 patients were excluded due to the lack of longitudinal thyrotropin measurements. Among 867 patients (557 64.2% female; mean SD age, 48.5 16.5 years) treated with a median (range) cumulative dose of 151 (30-1600) mCi radioactive iodine, disease progression was observed in 293 patients (33.8%), and 34 patients (3.9%) died; thus, the study was underpowered in death events. Thyrotropin suppression was not associated with improved PFS at landmarks 1.5 (P=.41), 3.0 (P=.51), and 5.0 (P=.64) years. At 1.5 and 3.0 years, older age (hazard ratio HR, 1.06; 95% CI, 1.03-1.08 and HR, 1.05; 95% CI, 1.01-1.08, respectively), lateral neck lymph node metastases (HR, 4.64; 95% CI, 2.00-10.70 and HR, 4.02; 95% CI, 1.56-10.40, respectively), and distant metastases (HR, 7.54; 95% CI, 3.46-16.50 and HR, 7.10; 95% CI, 2.77-18.20, respectively) were independently associated with subsequent time to progression, while at 5.0 years, PFS was shorter for patients with lateral neck lymph node metastases (HR, 3.70; 95% CI, 1.16-11.90) and poorly differentiated histology (HR, 71.80; 95% CI, 9.80-526.00). Conclusions and Relevance: Patients with intermediate- and high-risk DTC might not benefit from thyrotropin suppression. This study provides the justification for a randomized trial.